Ceralifimod (ONO-4641) is an oral, selective Sphingosine 1-phosphate receptor 1 and 5 agonist. It was studied in the phase 2 trials for the treatment of multiple sclerosis, however, further, development was discontinued.

Withaferin A is one of the most bioactive phytoconstituents of Withania somnifera, a well-known herb in Ayurvedic medical tradition of India. Due to the lactonal steroid's potential to modulate multiple oncogenic pathways, Withaferin A has gained much attention as a possible anti-neoplastic agent. Systematic research on the evaluation of anticancer activities of withaferin A was started around the 1970s. Since then, a large number of studies have demonstrated the ability of withaferin A to suppress the in vivo growth of various human cancer cells’ xenograft tumors as well as experimentally induced carcinogenesis in different rodent models. It has being reported that withaferin-A reduced the growth of human prostate cancer (PC3) cells tumor xenograft in nude mice by blocking the tumor angiogenesis and inducing intratumoral apoptosis. According to this study, i.p. administration of withaferin-A caused regression of implanted tumor cells by decreasing the expression of angiogenesis marker CD31, inducing the expression of proapoptotic protein Bax, and activating caspase-3 via inhibition of nuclear factor-κB (NF-κB) signaling pathway. In a separate study, intratumoral administration of withaferin-A arrested PC3 cells’ xenograft tumor growth in mice by inducing tumor cell death via upregulation of prostate apoptosis response-4 (Par-4). Anticancer activity of withaferin-A has also being demonstrated for gynecological cancer, melanoma, thyroid, gastrointestinal and other types of cancer. Mechanistic basis of the anticancer effects of withaferin-A includes: (1) reinforcement of cellular antioxidant and/or detoxification system; (2) suppression of inflammatory pathways; (3) selective inhibition of tumor cell proliferation and induction of apoptosis; (4) suppression of tumor angiogenesis; (5) blockade of epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastasis; (6) alteration of tumor cell metabolism; (7) immunomodulation; and (8) eradication of cancer stem cells.

Cinobufotalin, the bufadienolide isolated from toad venom, has displayed antitumor activities in many in vitro systems. It has been shown that cinobufotalin induced significant apoptosis in cultured human lymphoma U-937 cells. It induced DNA fragmentation, mitochondrial membrane potential decrease, and reactive oxygen species (ROS) production in U-937 cells. Cinobufotalin induces cytotoxic effect in cultured lung cancer cells. Cinobufotalin (1/5 mg/kg, i.p. twice daily, for 7 days) significantly inhibited A549 xenograft growth in mice. Further, same cinobufotalin administration improved mice survival at week five. Cinobufotalin administration didn’t significantly affect mice body weight, indicating the relative safety of this regimen. Thus, cinobufotalin inhibits A549 xenograft growth in vivo and improves mice survival.

4‐Chlorokynurenine (AV-101) is a neuropharmaceutical drug candidate in development for the treatment of major depressive disorder. Pharmacology studies conducted in rodent models have demonstrated AV-101’s antihyperalgesic activity in models of facilitated pain processing was seen at serum concentrations ranging from 150–300 M. In addition, AV-101 has been shown to be neuroprotective activity against an intrahippocampal injection of quinolinic acid, reductions in seizures, and antidepressive activity. An oral prodrug, AV-101, which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain. The two Phase 1 studies were designed to assess the safety and pharmacokinetics of AV-101, over a wide dose range, after daily dosing for 14-days. AV-101 has excellent safety and PK characteristics providing support for advancing AV-101 into Phase 2 studies in neuropathic pain.

Solasodine is an aglycone of solamargine and solasonine, which are the major solasodine glycosides present in numerous species of the solanaceae family including potato, tomato or garden egg plant etc. In Phase II clinical trial was shown that solasodine glycosides exhibit anticancer activity against skin cancer. The effects of aglycone solasodine on cancer cells have also been investigated. Solasodine inhibits the growth of human colon and liver cancer cell. In addition, solasodine effectively inhibits proliferation of HER2-overexpressing breast cancer cells and inhibits invasion of human lung cancer cells. Solasodine possesses CNS activities such as antipyretic, anticonvulsant and memory enhancing effects. Also, solasodine has been found to possess diuretic, antifungal, hepatoprotective, immunomodulatory, anti-spermatogenetic and antiandrogenic effects.

L-DEPRENYL-D2 C-11 is a selective irreversible inhibitor of monoamine oxidase B (Mao-B) which labels functionally active enzyme. It is used as a positron emission tomography radioligand for measurement of the Mao-B activity in vivo brain.

NS-2359, an orally active, triple monoamine reuptake inhibitor that inhibits the reuptake of dopamine, noradrenaline and serotonin, is being developed by Saniona and the Treatment Research Center (TRC) at the University of Pennsylvania for the treatment of Cocaine abuse. NS-2359’s pharmacological profile means that it may be able to reduce cocaine withdrawal symptoms, reduce cocaine craving and reduce cocaine-induced euphoria. Previously NS-2359 was in clinical trials for the treatment of attention-deficit hyperactivity disorder and major depressive disorder, but development was discontinued due to lack of effectiveness.

CYR-101 (MIN-101) is a cyclic amide derivative that has high equipotent affinities for 5-HT2A and sigma-2 receptors (Ki of 7.53 nM and 8.19 nM for 5-HT2A and sigma-2, respectively). MIN-101 also shows binding affinity for a1-adrenergic receptors but low or no affinity for muscarinic, cholinergic, and histaminergic receptors. MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients. The drug is in phase II clinical trials for the treatment of Schizophrenia.

[11C]-SCH-442416 was designed and synthesized by scientists at the University of Milano-Bicocca with the intent of development as a PET imaging probe. [11C]-SCH-442416 demonstrates a selective high affinity as an antagonist of the A2A Adenosine Receptor with a Ki of 0.48 nM. [11C]-SCH-442416 has demonstrated the ability to cross the blood-brain barrier and has been used as an imaging agent in a number of animals studies and at least one clinical trial in healthy human volunteers. It should be noted that the non-radio labeled form of SCH-442416 has been investigated in rats for the treatment of addictive behaviors.

Filorexant (MK-6096) is a novel, structurally distinct dual orexin receptor antagonist, conclusively validates orexin signalling mechanism as a specific and effective target for the treatment of insomnia and potentially other disorders in which sleep/wake dysregulation occurs. Also, it is being investigated as a possible agent against diabetic neuropathies, major depressive disorder and for the a migraine prophylaxis. Detected adverse events are: sleep-onset paralysis, excessive daytime sleepiness. As of May 2015, filorexant is no longer listed on Merck's online development pipeline.